pharmaceutics Review Additive Manufacturing of Oral Tablets: Technologies, Materials and Printed Tablets Alperen Abaci 1,†, Christina Gedeon 1,†, Anna Kuna 1 and Murat Guvendiren 1,2,* 1 Otto H. York Department of Chemical and Materials Engineering, New Jersey Institute of Technology, Newark, NJ 07102, USA; [email protected] (A.A.); [email protected] (C.G.); [email protected] (A.K.) 2 Department of Biomedical Engineering, New Jersey Institute of Technology, Newark, NJ 07102, USA * Correspondence: [email protected]; Tel.: +973-596-2932 † These authors contributed to this work equally. Abstract: Additive manufacturing (AM), also known as three-dimensional (3D) printing, enables fabrication of custom-designed and personalized 3D constructs with high complexity in shape and composition. AM has a strong potential to fabricate oral tablets with enhanced customization and complexity as compared to tablets manufactured using conventional approaches. Despite these advantages, AM has not yet become the mainstream manufacturing approach for fabrication of oral solid dosage forms mainly due to limitations of AM technologies and lack of diverse printable drug formulations. In this review, AM of oral tablets are summarized with respect to AM technology. A detailed review of AM methods and materials used for the AM of oral tablets is presented. This article also reviews the challenges in AM of pharmaceutical formulations and potential strategies to overcome these challenges. Keywords: 3D printing; polymer; hydrogel; pharmaceutical; precision medicine; drug delivery Citation: Abaci, A.; Gedeon, C.; Kuna, A.; Guvendiren, M. Additive Manufacturing of Oral Tablets: Technologies, Materials and Printed 1. Introduction Tablets. Pharmaceutics 2021, 13, 156. The majority of the drugs are administered orally in the form of a solid dosage form. https://doi.org/10.3390/ Oral tablets offer dose precision, chemical and microbial stability, controlled drug release pharmaceutics13020156 profiles, and ease of administration [1–3]. Oral tables can easily be carried by the patient, making them available when needed (on-demand administration). Despite these advan- Academic Editor: Dimitrios tages, conventional tablet manufacturing methods include time- and labor consuming A. Lamprou procedures, including a multitude of steps: (i) bulk powder material handling and mixing Received: 29 December 2020 of excipients and active pharmaceutical ingredients (APIs), (ii) powder processing such as Accepted: 21 January 2021 compression and wet or dry granulation, (iii) tablet compression and testing, (iv) tablet Published: 25 January 2021 relaxation, (v) tablet coating, and (vi) tablet collection and handling [4–6]. Continuous (oral solid dosage) manufacturing (CM) enabled full integration of bulk powder handling to Publisher’s Note: MDPI stays neutral final tablet product, yet CM offers limited dose flexibility and tablet customizability [7,8]. with regard to jurisdictional claims in Additive manufacturing (AM) technology enables the fabrication of custom-designed oral published maps and institutional affil- tablets with high architectural, structural, and compositional complexity [9–11], and could iations. potentially lead to a paradigm shift in tablet manufacturing from a one fit all approach to personalized medicine. Additive manufacturing (AM), also known as 3D printing, is a layer-by-layer fabri- cation method utilizing a printable material, or ink, to create a 3D object from a digital Copyright: © 2021 by the authors. image developed via computer-aided design (CAD). Multi-material AM approaches enable Licensee MDPI, Basel, Switzerland. precise positioning of a multitude of distinct materials or combination of materials to This article is an open access article create compositional complexity, including multi-phasic 3D constructs with each phase distributed under the terms and constituting a distinct composition, as well as constructs with compositional gradients. conditions of the Creative Commons Attribution (CC BY) license (https:// Note that the printability of a material is directly determined by the AM technology, which creativecommons.org/licenses/by/ also dictates the form of the ink, including filament, solution, melt, slurry, or powder [12]. 4.0/). Pharmaceutics 2021, 13, 156. https://doi.org/10.3390/pharmaceutics13020156 https://www.mdpi.com/journal/pharmaceutics Pharmaceutics 2021, 13, 156 2 of 27 Overall, AM could offer significant design flexibility in oral tablet manufacturing by en- abling custom-designed tablets matching the target patient for personalized medicine. Tablets could be personalized by tailoring the target dose for single APIs or combination of APIs and their release profile according to the patient’s age and weight, and/or the severity of the disease [13]. In addition, AM could potentially be instrumental for early-phase drug development scenarios including evaluation of oral dosage forms for preclinical studies (including dose flexibility), exploration of custom designs (shape, porosity, and composi- tion), and on-demand manufacturing (at clinical site) as well as an overall reduction in utilization of resources. Despite these potential advantages, there is a big gap in additively manufactured oral tablets in the market after the first 3D-printed tablet in the market, Spritam®, was approved by the United States Food and Drug Administration (FDA) in 2016. In this review, we summarize AM technologies used in oral tablet fabrication, widely used materials in additively manufactured oral tablet formulations, and tablets printed for each AM technology. We also present the challenges in AM of pharmaceutical formulations and potential strategies to overcome these challenges. 2. AM Technologies In this review, the AM technologies used for oral tablet printing are classified under four main groups: extrusion-based, vat photopolymerization-based, droplet-based, and powder-based printing (Figure1). Figure 1. The additive manufacturing technologies used in oral tablet fabrication. Extrusion-based printing includes filament printing, commonly known under the trademark name fused deposition modeling (FDM), and direct ink writing (DIW). In extrusion-based printing, the ink, i.e., the printable material in the form of a viscous melt or liquid (or slurry), is extruded through a nozzle forming individual struts (or lines) that solidify onto the build substrate. The nozzle follows a custom-designed line path determined by the g-code (computer-aided design) to form a 3D object in a layer-by-layer manner. For FDM, the ink is a thermoplastic solid filament. This filament is pulled into a hot nozzle and extruded as a melt. For DIW, the ink is a viscous melt, liquid or slurry (30–6 × 107 mPa.s). When polymer solutions are used as an ink, low boiling point solvents (such as dichloromethane (DCM) or tetrahydrofuran (THF)) are preferred to ensure rapid evaporation of the extruded ink to form a solid polymer [14]. Powder-based printing technology includes selective laser sintering (SLS), which allows printing of powders (polymers, ceramics, and metals, as well as their composites). In SLS, a laser beam moves over the powder bath raising the temperature of the powder particles on its path to sinter or fuse the particles spatially. Once a single layer is formed, the build platform moves down and a fresh layer of powder is applied from the top, and Pharmaceutics 2021, 13, 156 3 of 27 the process is repeated. The ink is in the form of a fine powder (10 to 100 µm in diameter) with good flow properties within the bed system. SLS machines usually require a large amount of powder, and they are not readily available [15,16]. Droplet-based printing technologies include inkjet printing and binder jetting (BJ). The ink is a low viscosity solution (viscosity below 10 cP (mPa.s)), which is ejected as an individual droplet (25–100 µm in diameter; 1–100 picoliters) [17]. In inkjet printing, the droplet is required to be placed on the print substrate and coalesce with the adjacent droplets to form a solid line. Similar to extrusion-based printing, the nozzle follows a custom-designed line path to form a 3D object in a layer-by-layer manner. The ink is usually exposed to high shear rates (0.1–1 × 106 s−1), and the inks should have a surface tension in the range of 28–350 mN·m−1 to ensure proper ejection from the nozzle and shape of the droplet on the substrate [18–21]. Similar to the DIW process, the liquid-to-solid transformation is crucial to determine the final shape of the printed structure. When the ink is printed directly on a powder bath surface, the process is referred to as BJ. Note that BJ could also be considered as powder-based printing. In BJ, ink is a binding solution which binds the powder particles together. In this process, the ink droplets bind the powders to form a layer. The powder platform moves down and a fresh powder layer is brought on top, and the process repeats itself [22]. In vat photopolymerization-based printing, the ink is a photocurable viscous liquid (i.e., a prepolymer, macromer, or a monomer), and photocuring refers to light-induced poly- merization (photopolymerization) and/or crosslinking (photocrosslinking). In traditional stereolithography (SLA) printing, a beam of light (e.g., UV or laser) moves over the vat and cures ink spatially. The beam follows a pattern (defined by the g-code) to create a layer. After each layer is completed, the build stage moves down into the vat. Recent SLA printers are inverted, thus pulling the printed layer up, which significantly